title: The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats.
abstract: OBJECTIVE
  The iron chelator Dp44mT is a potent topoisomerase IIα inhibitor with novel anticancer activity. Doxorubicin (Dox), the current front-line therapy for breast cancer, induces a dose-limiting cardiotoxicity, in part through an iron-mediated pathway. We tested the hypothesis that Dp44mT can improve clinical outcomes of treatment with Dox by alleviating cardiotoxicity.
  
  
  METHODS
  The general cardiac and renal toxicities induced by Dox were investigated in the presence and absence of Dp44mT. The iron chelating cardioprotectant Dexrazoxane (Drz), which is approved for this indication, was used as a positive control. In vitro studies were carried out with H9c2 rat cardiomyocytes and in vivo studies were performed using spontaneously hypertensive rats.
  
  
  RESULTS
  Testing of the GI(50) profile of Dp44mT in the NCI-60 panel confirmed activity against breast cancer cells. An acute, toxic dose of Dox caused the predicted cellular and cardiac toxicities, such as cell death and DNA damage in vitro and elevated cardiac troponin T levels, tissue damage, and apoptosis in vivo. Dp44mT alone caused insignificant changes in hematological and biochemical indices in rats, indicating that Dp44mT is not significantly cardiotoxic as a single agent. In contrast to Drz, Dp44mT failed to mitigate Dox-induced cardiotoxicity in vivo.
  
  
  CONCLUSIONS
  We conclude that although Dp44mT is a potent iron chelator, it is unlikely to be an appropriate cardioprotectant against Dox-induced toxicity. However, it should continue to be evaluated as a potential anticancer agent as it has a novel mechanism for inhibiting the growth of a broad range of malignant cell types while exhibiting very low intrinsic toxicity to healthy tissues.
authors.affiliation: Laboratory of Biochemistry, Center for Drug Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Building 29A, Room 2A-11, Bethesda, MD 20892, USA. ashutosh.rao@fda.hhs.gov
authors.forename: V Ashutosh
authors.initials: VA
authors.lastname: Rao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Klein
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Dickey
authors.forename: Eugene
authors.initials: E
authors.lastname: Herman
authors.forename: Emily B
authors.initials: EB
authors.lastname: Shacter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013882:Thiosemicarbazones / Q000494:pharmacology*; D020107:Troponin T / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; D020107:Troponin T; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; D004317:Doxorubicin